This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The ability of proteins to discriminate among nucleic acid sequences is at the heart of gene regulation and translational control in all organisms. Here we propose detailed x-ray crystallographic studies of protein-DNA and protein-RNA complexes of bacterial, human, and archaeal origins which elucidate this common theme in a variety of important biological contexts. Systems to be studied for which crystal structures of components to a larger assembly have been determined, or for which native enzymes/mutants have been solved are the transcriptional regulator Lrp, the glutaminyl and cysteinyl-tRNA synthetases (CysRS), and the DNA restriction-modification enzymes M.HhaI and EcoRV. Newer projects for which crystals are available, or for which protein-nucleic acid complexes are being screened for crystallization, are the human CysRS, two enzymes from a novel tRNA biosynthetic pathway in M. mazei, and tRNA complexes with isozymes of a hydrogenase from the methanogenesis pathway of M. jannaschii, which may play a role in regulating anaerobic methane production.